The sigma receptor includes at least two subtypes, σ1 and σ2. (Marriott et al., JPET, 343:578-586 (2012); Marriott et al., Bioorg. Med. Chem., 20:6856-6861 (2012)). The sigma receptor is an intracellular receptor that is present throughout the human body, including the central nervous system and peripheral organs. (Marriott et al., JPET, supra.). For example, the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), which is known to physically associate with the outer mitochondria membrane (OMM), consists of ER subdomains enriched with σ1 receptors. (Hayashi and Su, Subcell Biochem., 51:381-398 (2010).
The MAM may play an important role in supplying calcium to mitochondria as well as in lipid synthesis (e.g., phospholipids, cholesterol). (Hayashi and Su, Subcell Biochem., 51:381-398 (2010). In addition, cholesterol transported from the OMM to the inner mitochondrial membrane (IMM) is the primary step (the rate-limiting step) in steroidogenesis. (Bose et al., N. Engl. J. Med., 335:1870-1878 (1996); Marriott et al., JPET, supra.). Cholesterol is transported from the OMM to the IMM where it is catalyzed to form pregnenolone, which is subsequently transported back to the ER for the synthesis of several other steroids. (Miller and Bose, J. Lipid Res., 52:2111-2135 (2011)). Transport of cholesterol to the site of steroidogenesis may be facilitated by steroidogenic acute regulatory protein (StAR), which interacts with voltage-dependent anion channel (e.g., VDAC1) at the OMM. (Bose et al., J. Biol. Chem., 283:8837-8845) (2008)). The sigma receptor may also play a role, as transfection of dominant-negative σ-1 receptors has been shown to disrupt the compartmentalization of cholesterol at the MAM. (Hayashi and Su, supra.).
The sigma receptor has also been investigated as a target for therapeutics in a variety of diseases. For example, the σ1 receptor has been investigated as a target for therapeutics in addiction, amnesia, pain, depression, Alzheimer's disease, schizophrenia, stroke, retinal neural degeneration, HIV infection, and cancer. (Maurice et al., Pharmacol. Ther., 124:195-206 (2009); Hayashi et al., Expert Opin. Ther. Targets, 15:557-577 (2011)). In one example, the σ1 receptor ligand dimemorfan (with an affinity of 151 nM) has been shown to block the amnesic effects induced by β25-35-amyloid peptide treatment in mice. (Maurice et al., supra.). In another example, the σ1 receptor ligand donepezil (with an affinity of 14.6 nM) has been used to treat Alzheimer's Disease. (Maurice et al., supra.). In a further example, σ2 ligands have been shown to induce cancer cell death, and combining σ2 receptor selective ligands with gemcitabine chemotherapy in vivo or with doxorubicin in several in vitro cancer cell lines demonstrated an additive effect in the blocking of tumor growth. (Niso, J. Cancer Biol. Res., 1:1007 (2013).